Bone Marrow Transplantation as a Future Therapeutic Strategy for Idiopathic Pulmonary Fibrosis: Lessons from Hematopoietic Aging

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited therapeutic options. Lung transplantation is the only curative treatment, but it is rarely available due to a lack of suitable donors. In a recent publication in Science Immunology, Farhat et al. demonstrated that bone marrow transplantation from young donors alleviates fibrosis by restoring immune resolution in aged hosts in animal models. Aged hematopoietic cells exacerbate fibrosis through the persistence of inflammatory macrophages and impaired Treg-derived IL-10, highlighting bone marrow rejuvenation as a potential treatment strategy for IPF.

Keywords

Idiopathic pulmonary fibrosis (IPF) / Bone marrow transplantation (BMT) / Monocyte-derived alveolar macrophage (Mo-AM) / Tregs / IL-10

Acknowledgments

We thank lab members for their insightful and helpful discussions.

Author Contributions

X.L. wrote the original manuscript, prepared the figure, reviewed and edited the manuscript.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Funding

This research was funded by the American Heart Association award 24CDA1268568 and the Pulmonary Fibrosis Foundation Scholars Program 1272558.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: Patterns and perpetrators. J. Clin. Investig. 2012, 122, 2756-2762. doi:10.1172/JCI60323.

[2] Richeldi L, Collard HR, Jones MG.Idiopathic pulmonary fibrosis. Lancet 2017, 389, 1941-1952. doi:10.1016/S0140-6736(17)30866-8.

[3] Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, et al.Idiopathic pulmonary fibrosis. Nat. Rev. Dis. Primers 2017, 3, 17074. doi:10.1038/nrdp.2017.74.

[4] Rojas M, Mora AL, Kapetanaki M, Weathington N, Gladwin M, Eickelberg O. Aging and Lung Disease. Clinical Impact and Cellular and Molecular Pathways. Ann. Am. Thorac. Soc. 2015, 12, S222-S227. doi:10.1513/AnnalsATS.201508-484PL.

[5] Hauer ME.Population projections for U.S. counties by age, sex, and race controlled to shared socioeconomic pathway. Sci. Data 2019, 6, 190005. doi:10.1038/sdata.2019.5.

[6] Swaminathan AC, Hellkamp AS, Neely ML, Bender S, Paoletti L, White ES, et al. Disparities in Lung Transplant among Patients with Idiopathic Pulmonary Fibrosis. Ann. Am. Thorac. Soc. 2022, 19, 981-990. doi:10.1513/AnnalsATS.202105-589OC.

[7] Mason DP, Brizzio ME, Alster JM, McNeill AM, Murthy SC, Budev MM, et al. Lung transplantation for idiopathic pulmonary fibrosis. Ann. Thorac. Surg. 2007, 84, 1121-1128. doi:10.1016/j.athoracsur.2007.04.096.

[8] Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, et al. Type 2 alveolar cells are stem cells in adult lung. J. Clin. Investig. 2013, 123, 3025-3036. doi:10.1172/JCI68782.

[9] Heukels P, Moor CC, von der Thusen JH, Wijsenbeek MS, Kool M. Inflammation and immunity in IPF pathogenesis and treatment. Respir. Med. 2019, 147, 79-91. doi:10.1016/j.rmed.2018.12.015.

[10] Shenderov K, Collins SL, Powell JD, Horton MR. Immune dysregulation as a driver of idiopathic pulmonary fibrosis. J. Clin. Investig. 2021, 131, 2. doi:10.1172/JCI143226.

[11] Pokhreal D, Crestani B, Helou DG. Macrophage Implication in IPF: Updates on Immune, Epigenetic, and Metabolic Pathways. Cells 2023, 12, 2193. doi:10.3390/cells12172193.

[12] Raghu G, Brown KK, Costabel U, Cottin V, du Bois RM, Lasky JA, et al. Treatment of Idiopathic Pulmonary Fibrosis with Etanercept An Exploratory, Placebo-controlled Trial. Am. J. Resp. Crit. Care 2008, 178, 948-955. doi:10.1164/rccm.200709-1446OC.

[13] Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ, Clinical IPF. Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis. N. Engl. J. Med. 2012, 366, 1968-1977. doi:10.1056/NEJMoa1113354.

[14] Byrne AJ, Maher TM, Lloyd CM. Pulmonary Macrophages: A New Therapeutic Pathway in Fibrosing Lung Disease? Trends. Mol. Med. 2016, 22, 303-316. doi:10.1016/j.molmed.2016.02.004.

[15] Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J. Exp. Med. 2017, 214, 2387-2404. doi:10.1084/jem.20162152.

[16] Perrot CY, Karampitsakos T, Herazo-Maya JD. Monocytes and macrophages: Emerging mechanisms and novel therapeutic targets in pulmonary fibrosis. Am. J. Physiol. Cell. Physiol. 2023, 325, C1046-C1057. doi:10.1152/ajpcell.00302.2023.

[17] McQuattie-Pimentel AC, Budinger GRS, Ballinger MN. Monocyte-derived Alveolar Macrophages: The Dark Side of Lung Repair? Am J Respir Cell Mol Biol 2018, 58, 5-6. doi:10.1165/rcmb.2017-0328ED.

[18] Joshi N, Watanabe S, Verma R, Jablonski RP, Chen CI, Cheresh P, et al. A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages. Eur. Respir. J. 2020, 55, 1. doi:10.1183/13993003.00646-2019.

[19] Kean LS, Blazar BR. Major breakthroughs in hematopoietic stem cell transplantation and future challenges in clinical implementation. J. Clin. Investig. 2024, 134, e179944. doi:10.1172/JCI179944.

[20] Kingsley PD, Rust ET, Kingsley AJ, Pinney JJ, Rivera-Escalera F, Bennett CP, et al. Tissue-Resident Macrophages in the Bone Marrow Comprise a Diverse Cellular Population Derived from Hematopoietic Stem Cells. Blood 2023, 142, 3910. doi:10.1182/blood-2023-188067.

[21] Nasser H, Adhikary P, Abdel-Daim A, Noyori O, Panaampon J, Kariya R, et al. Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages. Cell Death Discov. 2020, 6, 63. doi:10.1038/s41420-020-00300-3.

[22] Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 2016, 7, 10321. doi:10.1038/ncomms10321.

[23] Alibhai FJ, Li RK. Targeting aged bone marrow for systemic rejuvenation. Aging 2020, 12, 2024-2025. doi:10.18632/aging.102838.

[24] Hou J, Chen KX, He C, Li XX, Huang M, Jiang YZ, et al. Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence. Nat. Aging 2024, 4, 1562-1581. doi:10.1038/s43587-024-00694-0.

[25] Farhat A, Radhouani M, Deckert F, Zahalka S, Pimenov L, Fokina A, et al. An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence. Sci. Immunol. 2025, 10, eadk5041. doi:10.1126/sciimmunol.adk5041.

[26] Guenin-Mace L, Konieczny P, Naik S. Immune-Epithelial Cross Talk in Regeneration and Repair. Annu. Rev. Immunol. 2023, 41, 207-228. doi:10.1146/annurev-immunol-101721-062818.

[27] Choi J, Park JE, Tsagkogeorga G, Yanagita M, Koo BK, Han N, et al. Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration. Cell. Stem. Cell. 2020, 27, 366. doi:10.1016/j.stem.2020.06.020.

[28] McQuattie-Pimentel AC, Ren Z, Joshi N, Watanabe S, Stoeger T, Chi M, et al. The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging. J. Clin. Investig. 2021, 131, 4. doi:10.1172/JCI140299.

[29] Lv JJ, Zhang C, Liu XX, Gu CY, Liu YD, Gao YH, et al. An aging-related immune landscape in the hematopoietic immune system. Immun. Aging. 2024, 21, 3. doi:10.1186/s12979-023-00403-2.

[30] Yanik G, Cooke KR. The lung as a target organ of graft-versus-host disease. Semin. Hematol. 2006, 43, 42-52. doi:10.1053/j.seminhematol.2005.09.004.

[31] Ernst M, Inglese M, Scholz GM, Harder KW, Clay FJ, Bozinovski S, et al. Constitutive activation of the Src family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. J. Exp. Med. 2002, 196, 589-604. doi:10.1084/jem.20020873.

[32] Hu M, Che P, Han X, Cai GQ, Liu G, Antony V, et al. Therapeutic targeting of SRC kinase in myofibroblast differentiation and pulmonary fibrosis. J. Pharmacol. Exp. Ther. 2014, 351, 87-95. doi:10.1124/jpet.114.216044.

[33] Leuschner G, Reiter F, Stocker F, Crispin A, Kneidinger N, Veit T, et al. Idiopathic Pulmonary Fibrosis Among Young Patients: Challenges in Diagnosis and Management. Lung 2018, 196, 401-408. doi:10.1007/s00408-018-0123-9.

[34] Raghu G, Chen SY, Hou Q, Yeh WS, Collard HR. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur. Respir. J. 2016, 48, 179-186. doi:10.1183/13993003.01653-2015.